tag:blogger.com,1999:blog-2915315621935320192024-03-13T18:12:42.819+05:30Cell-Mechanics Laboratory, IIT MadrasWelcome to the Cell-Mechanics Lab, Department of Applied Mechanics and Biomedical Engineering, IIT Madras. Cell Mechanics Laboratory, IIT Madrashttp://www.blogger.com/profile/09776321590790163735noreply@blogger.comBlogger3125tag:blogger.com,1999:blog-291531562193532019.post-84926076311223353992022-08-03T08:48:00.002+05:302023-09-29T10:32:32.856+05:30Research<p> </p><p style="text-align: left;"></p><p class="has-primary-color has-text-color">The Cell-Mechanics lab in the Department of Applied Mechanics and Biomedical Engineering, IIT
Madras, focuses on studying the mechanics behind health and disease, at
cellular and sub-cellular scales. Borrowing upon principles from
physical and mathematical sciences, we explore human biology
that is responsible for, and is affected by, forces of interaction
between mammalian cells and their surroundings. </p><p class="has-primary-color has-text-color"> </p><div class="wp-container-2 wp-block-columns" data-carousel-extra="{"blog_id":162368037,"permalink":"https:\/\/cellphys.wordpress.com\/?page_id=82"}" style="text-align: left;"><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiJYzXzDeObuwmed_45QSLdYJ5Jdn3PNyLYZGameosnSg4FcXw18nemfEeVq5T52iavRNAzS31OhrT5blfnPoG4TTpw2rEkEAO07hUlnbLE6CjfmPyb8Jyl5M7KkWHKxQpYoQ6jSuEIy3j-m-O4x-ZM8RjiysYQxo2C1oe0EJwpeiOwIEyEDz1EBQ/s635/testpic.png" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="525" data-original-width="635" height="453" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiJYzXzDeObuwmed_45QSLdYJ5Jdn3PNyLYZGameosnSg4FcXw18nemfEeVq5T52iavRNAzS31OhrT5blfnPoG4TTpw2rEkEAO07hUlnbLE6CjfmPyb8Jyl5M7KkWHKxQpYoQ6jSuEIy3j-m-O4x-ZM8RjiysYQxo2C1oe0EJwpeiOwIEyEDz1EBQ/w548-h453/testpic.png" width="548" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><i>Focus
areas of Cell-Mechanics lab: Metastatic extravasation and invasion,
Extracellular vesicles, Blood-cell assay development, Alveolar
transport, and Bio-materials development</i><br /></td></tr></tbody></table><br /><div class="separator" style="clear: both; text-align: center;"><p class="has-primary-color has-text-color" style="margin-left: 1em; margin-right: 1em;"></p></div><div class="wp-container-1 wp-block-column" data-carousel-extra="{"blog_id":162368037,"permalink":"https:\/\/cellphys.wordpress.com\/?page_id=82"}" style="flex-basis: 100%;"><p class="has-primary-color has-text-color"></p><p class="has-primary-color has-text-color">Some of the currently running research endeavors are in the field of (but not limited to):<br /></p>
<p class="has-primary-color has-text-color"></p>
<ul style="text-align: left;"><li><b><a href="#cardioonco" target="">Cardio-oncology:</a> </b>Examining the cross-talk between<b> </b>hypertension therapy and metastasis. <br /></li><li><b><a href="#microenv">Approximating the cellular micro-environment:</a> </b>Recreating biophysical features specific to solid-tumor micro-environment, in experimental cell-culture model. </li><li><a href="#phycell"><b>Physics of cell-migration</b></a> through extracellular matrices, and designing of efficient therapeutic schemes. </li></ul><p>Related areas of interest include:<b> </b></p><ul style="text-align: left;"><li><b>Extravasation mechanics</b>, for circulating tumor cells. </li></ul><ul style="text-align: left;"><li><b>Extracellular vesicles (EV): </b>Characterization of secreted EVs during of pulmonary injury </li></ul><p></p><ul style="text-align: left;"><li><b>Biomaterials development:</b> To expose cells to varying mechanical environments of matrix stiffness, architecture, and ligands. </li></ul><p></p><ul style="text-align: left;"><li><b>Visco-elasticity: </b>of orthotropic collagenous scaffolds, plasma-membrane, extracellular-matrix, etc.<br /></li></ul><p></p><ul style="text-align: left;"><li><b>Resistive pulse-sensing</b> of suspended mammalian cells such as blood-cells.<br /></li></ul><p> <br />Our collaborators include Physicists, Biologists, and Clinicians. Key skills that our research scholars develop are related to <b>mammalian
cell-culture, numerous modes of light-microscopy, soft-lithography,
instrumentation and signal processing, bio-material synthesis and
mechanical characterization, and optics.</b></p><h4 class="has-primary-color has-text-color" style="text-align: left;">(i)<b> <a id="cardioonco"> Cardio-oncology:</a> </b><br /></h4>
<p class="has-primary-color has-text-color"></p><table cellpadding="0" cellspacing="0" class="tr-caption-container" style="float: right;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjp1Cfq_9BFATCps4wUctCWKZaPBVgEu2mhJ8vy2OEVEGiaIfNQQzufgtdiNOuX7TLSSzKtKWWLj6SVqSYlHYFbB5wqUbhAQJtuEsgQDUlGT9x-OoqrfzPVXWHHzFqeSGfOF3j5IBqagZ6MomQdyogICJbgUTlZ5VYW6pTLwZax_DvucoiMfupRwg/s1352/Im9.tif" style="clear: right; margin-bottom: 1em; margin-left: auto; margin-right: auto;"><img border="0" data-original-height="467" data-original-width="1352" height="197" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjp1Cfq_9BFATCps4wUctCWKZaPBVgEu2mhJ8vy2OEVEGiaIfNQQzufgtdiNOuX7TLSSzKtKWWLj6SVqSYlHYFbB5wqUbhAQJtuEsgQDUlGT9x-OoqrfzPVXWHHzFqeSGfOF3j5IBqagZ6MomQdyogICJbgUTlZ5VYW6pTLwZax_DvucoiMfupRwg/w568-h197/Im9.tif" width="568" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><i>Extravasation
involves an orchestrated dance of mechanics of cellular traction,
membrane, and endothelial junctional integrity, each affected by
cardiovascular drugs. </i><br /></td></tr></tbody></table> </div><div class="wp-container-1 wp-block-column" data-carousel-extra="{"blog_id":162368037,"permalink":"https:\/\/cellphys.wordpress.com\/?page_id=82"}" style="flex-basis: 100%;">In
order to understand the crosstalk between cardiovascular drugs and
cancer-progression, we examine the drug-mediated mechanics of
metastatic stages such as loss of cell-to-cell adhesion, gain of
cell-to-substrate
adhesion, generation of cell-matrix traction, and extravasation of
cancer cell across endothelial mono-layer. Since endothelium is
frequently the target of cardio-mediatory drugs such as calcium-channel
blockers (used to treat hypertension), we quantify the effect of such
interventions on cancer-cell extravasation and endothelial junctional
integrity. Towards this, we characterize trans-endothelial electrical
resistance (TEER), transwell-assay for permeability, as well as direct
mechanical characterization of cells using optical tweezers. <i> </i></div><div class="wp-container-1 wp-block-column" data-carousel-extra="{"blog_id":162368037,"permalink":"https:\/\/cellphys.wordpress.com\/?page_id=82"}" style="flex-basis: 100%;"><br /><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiHy9lEEhIB45TnYFlGgz-2xb_UEmWOgctAfAz7kAp-IlMuqdCV1Yp-CF-qsBX23clXwmF1nKo-0iTFHBrHSQwINOPe77P6Im2hdr_W0OGZiwXxkFCTk3w1yVB1iKxDm_APpswKTchdH--_jc7mNjsXZ_lQjNbZPyoI_Ae3AUdIss0z3o3iz3poFw/s1442/Pictureg.png" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="585" data-original-width="1442" height="279" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiHy9lEEhIB45TnYFlGgz-2xb_UEmWOgctAfAz7kAp-IlMuqdCV1Yp-CF-qsBX23clXwmF1nKo-0iTFHBrHSQwINOPe77P6Im2hdr_W0OGZiwXxkFCTk3w1yVB1iKxDm_APpswKTchdH--_jc7mNjsXZ_lQjNbZPyoI_Ae3AUdIss0z3o3iz3poFw/w686-h279/Pictureg.png" width="686" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><i>Characterizing the membrane of
endothelial cells, during hypertension-therapy, using optical tweezers
(A), and endothelial integrity (B) using trans-endothelial electrical
resistance (TEER)</i></td></tr></tbody></table><i style="margin-left: 1em; margin-right: 1em;"><br /></i><h4 style="text-align: left;">(ii) <b><a id="microenv">Designing cellular micro-environment</a></b></h4>
<p class="has-primary-color has-text-color">During
metastatic migration, cancer cells are exposed to a multiscalar
anistropic microenvironment. We are generating tunable engineered
microenvironments that allow control over the characteristic properties
of cell-microenvironment. In the micrograph (B, below), we see a highly disordered
cell-compatible matrix created through processing of silk-fibroin
protein, approximating the ordered architecture of ECM surrounding a solid-tumor (A, below)<br /></p><p class="has-primary-color has-text-color"> <br /></p><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjofS6Ok0h91DQIpN4GsPeHXEage_UlFLb10G1-TZXmMwOT0vM9aZCJg2N2xESWWHki78f0kcPaS1JDw9mM6pgHvrtt7K_r90QBCxWM_m0g6p-WYjozBUWI1NX13YyHUcLO3ktrTdlA0u0uxZggjZJ7W7G3eRkYiTDz0bpD1xCKyBi2nvfBt1o3bA/s1776/Picture11.png" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="782" data-original-width="1776" height="258" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjofS6Ok0h91DQIpN4GsPeHXEage_UlFLb10G1-TZXmMwOT0vM9aZCJg2N2xESWWHki78f0kcPaS1JDw9mM6pgHvrtt7K_r90QBCxWM_m0g6p-WYjozBUWI1NX13YyHUcLO3ktrTdlA0u0uxZggjZJ7W7G3eRkYiTDz0bpD1xCKyBi2nvfBt1o3bA/w587-h258/Picture11.png" width="587" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><i>Design
of scaffolds for 3D models of cell-migration and growth, exhibiting
micro-architecture that approximates the anisotropy around solid tumors.</i></td></tr></tbody></table></div><div class="wp-container-1 wp-block-column" data-carousel-extra="{"blog_id":162368037,"permalink":"https:\/\/cellphys.wordpress.com\/?page_id=82"}" style="flex-basis: 100%;"><h4 class="has-primary-color has-text-color" style="text-align: left;"> </h4><h4 class="has-primary-color has-text-color" style="text-align: left;"> </h4><h4 class="has-primary-color has-text-color" style="text-align: left;">(iii) <b><a id="phycell">Physics of cell-migration</a><br /></b></h4>
<p class="has-primary-color has-text-color">We are interested in
quantifying the forces that a single or a cluster of cells exterts over a
2-D substrate in order to migrate effectively, and under varied
physiological/pathological conditions. The micrograph shows a sample
image from live-cell traction measurements we conducted for fibroblasts
migrating over tunable 2-D substrates.</p><p class="has-primary-color has-text-color"> </p><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiOnKFAJVPH-eZ9ymOSbujoivOiGaV2jmy38ztUhTX1yYp4aB7sEHbP5l_PkNDQw5KXco-dngeHYvVZ_ZP3MgZXZkYVf4k7idznPmz2nnzk5obwdc7hVqQ1yWYeT_HeXGb12QNR5fl3MJW2A26apCQ3HZkWR1K2MUNxgSR29soz4rTGM43etUXt4g/s968/celltrac.png" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="380" data-original-width="968" height="210" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiOnKFAJVPH-eZ9ymOSbujoivOiGaV2jmy38ztUhTX1yYp4aB7sEHbP5l_PkNDQw5KXco-dngeHYvVZ_ZP3MgZXZkYVf4k7idznPmz2nnzk5obwdc7hVqQ1yWYeT_HeXGb12QNR5fl3MJW2A26apCQ3HZkWR1K2MUNxgSR29soz4rTGM43etUXt4g/w532-h210/celltrac.png" width="532" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><i>We examine the traction force generated by cells, in both 2D and 3D, under various exogenous stimulatory cues.</i><br /></td></tr></tbody></table><br /><p></p><p class="has-primary-color has-text-color"> <u><span style="color: red;">For more information, please feel free to contact us via. email, send in your tweet (</span></u><u><span style="color: red;"><span class="css-901oao css-16my406 r-poiln3 r-bcqeeo r-qvutc0">@CellMech_IITM</span>) or send us your query through the contact-us link on the top-right of this page. </span></u><br /></p><p class="has-primary-color has-text-color"> </p><p> </p>
</div><br /><br />
</div><br /><br />Cell Mechanics Laboratory, IIT Madrashttp://www.blogger.com/profile/09776321590790163735noreply@blogger.com0tag:blogger.com,1999:blog-291531562193532019.post-4082903245042377292022-08-03T08:47:00.002+05:302022-11-14T10:24:47.636+05:30Resistive Pulse Sensing<h1 style="text-align: left;"><div style="line-height: 150%; text-align: justify;"><span style="text-align: left;"> </span></div></h1><p></p><p class="MsoNormal" style="line-height: 150%; text-align: justify;"><span lang="EN-GB" style="font-family: "Cambria Math",serif; mso-ansi-language: EN-GB;"><i>(Manoj Sivasubramaniapandian, PhD scholar, talks about resistive-pulse sensing, as applied to diagnostic applications. The writing is un-edited and open to comments)</i></span></p><p class="MsoNormal" style="line-height: 150%; text-align: justify;"><span lang="EN-GB" style="font-family: "Cambria Math",serif; mso-ansi-language: EN-GB;">Resistive
pulse sensing, as the name suggests, depends on the transient resistance changes
in proportion to the ion current as a micron to molecular-scale particle
transits a pore or a narrow conduit. The presence of the particle at the
constriction changes the current across the constriction, which is proportional
to the particle's size, charge, shape, and conductivity. Since Coulter (1953)
developed the technique for counting suspended particles in a fluid, the
technique has undergone rapid evolution. While the earlier approach employs a fixed-sized
pore that restricts the choice of particles significantly, Tunable Resistive Pulse
Sensing (TRPS) permits pore dimension tuning, thereby ensuring improved
analytical range and sensitivity. <o:p></o:p></span></p><h3 style="text-align: left;"><span style="font-family: "Calibri",sans-serif; font-size: 12.0pt; mso-ansi-language: EN-IN; mso-ascii-theme-font: minor-latin; mso-bidi-font-family: Latha; mso-bidi-language: AR-SA; mso-bidi-theme-font: minor-bidi; mso-fareast-font-family: Calibri; mso-fareast-language: EN-US; mso-fareast-theme-font: minor-latin; mso-hansi-theme-font: minor-latin;"><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEj4kR6LRx4sYmA6Y1oVh8P3shpC-GurIqJi5BTDRFL7E_I4HYQ2CEmGhIsmGsINNStIlm7Xn-nOFXgE_J4337oF3esbjuNdPJesOBROA7W4ldAfrcUZsywzcGqTHswD_PPv0_7z8Olq7UvVL4aMzkLhxqRxigiBWmIb1FYgeLslVVhxFOoHaRb5_A" style="margin-left: auto; margin-right: auto;"><img alt="" data-original-height="649" data-original-width="2214" height="178" src="https://blogger.googleusercontent.com/img/a/AVvXsEj4kR6LRx4sYmA6Y1oVh8P3shpC-GurIqJi5BTDRFL7E_I4HYQ2CEmGhIsmGsINNStIlm7Xn-nOFXgE_J4337oF3esbjuNdPJesOBROA7W4ldAfrcUZsywzcGqTHswD_PPv0_7z8Olq7UvVL4aMzkLhxqRxigiBWmIb1FYgeLslVVhxFOoHaRb5_A=w605-h178" width="605" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><p align="center" class="MsoNormal" style="margin-bottom: 6pt;"><i><span style="font-family: "Times New Roman",serif; mso-bidi-language: TA; mso-fareast-font-family: "Times New Roman"; mso-fareast-language: EN-GB;">Figure 1: a) Schematic of the
resistive pulse sensing setup, b) Current response as differently-sized particles
transit through a fixed-diameter pore / conduit, and c) Particles transiting a
tapered pore and the corresponding current response.<o:p></o:p></span></i></p></td></tr></tbody></table><br /><br /><!--[endif]--></span><!--[if mso & !supportInlineShapes & supportFields]><span
style='font-size:12.0pt;font-family:"Calibri",sans-serif;mso-ascii-theme-font:
minor-latin;mso-fareast-font-family:Calibri;mso-fareast-theme-font:minor-latin;
mso-hansi-theme-font:minor-latin;mso-bidi-font-family:Latha;mso-bidi-theme-font:
minor-bidi;mso-ansi-language:EN-IN;mso-fareast-language:EN-US;mso-bidi-language:
AR-SA'><v:shape id="_x0000_i1025" type="#_x0000_t75" style='width:483pt;
height:141.7pt'>
<v:imagedata croptop="-65520f" cropbottom="65520f"/>
</v:shape><span style='mso-element:field-end'></span></span><![endif]--></h3><div><p class="MsoNormal" style="line-height: 150%; text-align: justify;"><span lang="EN-GB" style="font-family: "Cambria Math",serif; mso-ansi-language: EN-GB;">The
forces acting on the particles in TRPS are predominantly electrophoretic,
electroosmotic, and fluidic. Parameters such as pore size, voltage and pressure
are precisely controlled to tweak the magnitude of these forces. Several theoretical
models aim to determine particles' size, charge, and concentration. However,
the current models suffer from over-simplification, and finite element
modelling of simple experimental observations proves challenging owing to the limited
understanding of the geometry and activation mechanism of the pore. The Maxwell
model is suitable for spherical particles, much smaller than the fixed pore
diameter. However, if the diameter is not uniform, as in a tapered pore, it
results in a non-linear electric field gradient. While Heins attempted to address
this non-linear gradient in resistance across the tapered pore, the Maxwell
model is often employed owing to its simplicity in determining the size and
position of the particle.<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: 150%; text-align: justify;"><span lang="EN-GB" style="font-family: "Cambria Math",serif; mso-ansi-language: EN-GB;">On
the other hand, the charge or zeta potential is derived from electrophoretic
mobility and depends only on the pulse duration and not the magnitude, thereby enabling
simultaneous deduction of size and charge. Also, the particle-by-particle
measurement approach allows for resolving multiple zeta potentials in a
subpopulation. Ideally, particle transport should be primarily electrophoretic
to measure the zeta potential. Therefore, it is essential that pressure, if
applied, remain low to measure the electrophoretic mobility reliably. Other factors
involving the solution property and the presence of charges along the pore wall
could contribute to uncertainties and may require passivation. In cases where a
surfactant is employed to aid particle-by-particle measurement, its effect on
the overall charge cannot be considered insignificant. Nevertheless, the assumptions
regarding the ionic charge distribution, homogenous electric field, and the transport
of particles along the central axis under uniform flow rate are not always valid.<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: 150%; tab-stops: 269.7pt; text-align: justify;"><span lang="EN-GB" style="font-family: "Cambria Math",serif; mso-ansi-language: EN-GB;">Besides
all these factors influencing the measurement, the technique faces several practical
challenges: a) the need for a specialized membrane apparatus and pressure
module to precisely control particle translocation. The accessible smaller pore
ranges are limited, and changing pore geometries result in measurement
uncertainties. The most predominantly used equipment developed by Izon Science
Ltd., New Zealand, has the smallest available pore size of 40 nm, b) non-specific
binding or occlusion of pores with aggregated particles and complex biological
fluids. The blockage causes non-linear drift or drop in the baseline current
during measurements and is increasingly challenging with particles of size 100
nm or less. Therefore, it becomes critical to condition the membrane with the
coating agent, wetting agent, sodium azide and PBS (Reagent kit from Izon
Science Ltd., New Zealand) to reduce non-specific particle-membrane
interactions and c) the need for calibration. Calibration with commercially
prepared and certified (for size) monodispersed beads, in conjunction with the actual
measurements and under the same context, including the buffer components, the stretch
of the pore, pressure, and voltage is critical.<o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: 150%; tab-stops: 269.7pt; text-align: justify;"><span lang="EN-GB" style="font-family: "Cambria Math",serif; mso-ansi-language: EN-GB;">Despite
all these challenges, TRPS finds varied applications in environmental
monitoring, biomedical research, and clinical diagnosis, to name a few. One
such application is the time-dependent study of Blundell et al. to understand
protein interaction with carboxyl functionalized beads that exhibits a shift in
the zeta potential with time and temperature. Protein interaction and formation
of the poorly delimited hard and soft corona layers is a dynamic process. It
depends on the particle's physicochemical properties (size, charge, surface
functionalization, and curvature) and system complexity (including pH,
composition, circulation time, and pressure). A lot remains to learn about the
control and prediction of such interactions, and it could be the fingerprint to
investigate pathogenesis or drug delivery. <o:p></o:p></span></p>
<p class="MsoNormal" style="line-height: 150%; tab-stops: 269.7pt; text-align: justify;"><span lang="EN-GB" style="font-family: "Cambria Math",serif; mso-ansi-language: EN-GB;"> </span></p>
<p class="MsoNormal" style="margin-left: 32.0pt; mso-layout-grid-align: none; mso-pagination: none; text-autospace: none; text-indent: -32.0pt;"><span lang="EN-GB" style="font-family: "Cambria Math",serif; mso-ansi-language: EN-GB;"> </span></p></div><h3 style="text-align: left;">Manoj Sivasubramaniapandian</h3><h4 style="text-align: left;">manoj@smail.iitm.ac.in<br /></h4>Cell Mechanics Laboratory, IIT Madrashttp://www.blogger.com/profile/09776321590790163735noreply@blogger.com0tag:blogger.com,1999:blog-291531562193532019.post-60558747617546584692022-07-06T21:37:00.005+05:302022-07-07T05:19:59.583+05:30Que, Meta-stasis?<h1 style="text-align: left;"> </h1><i>[If ideas are entities that trade from mind to mind, then writing is their currency. And disjointed writing, like soiled currency, often does not serve its purpose. The objective of these pages is to induce the habit of writing, aiming for efficient technical communication amongst our research-scholars. These writings are unedited and therefore open to direct feedback. <br /><br /> In this, very first article of our Commentary-series, Privita Edwina (PhD scholar) discusses metastasis and the importance of dormant tumor cells in context of cancer progression. We invite readers to send in their comments/critique using the contact-form to the left.]</i><p class="MsoNormal" style="line-height: 150%; text-align: justify;"><br /></p><p class="MsoNormal" style="line-height: 150%; text-align: justify;">In solid-tissues
such as skin or liver, cells are connected to the neighbouring cells or the
extracellular matrix (ECM) through the transmembrane proteins known as cell
adhesion molecules. These connections help the cell/tissue maintain its form
and function. The communication between the cell and its neighbours happens in
the form of biophysical and/or biochemical signalling. It is a two-way process
in which the cell generated signals are transferred to the surrounding matrix
or the neighbouring cells which in turn respond by signalling downstream
effectors and vice versa. When the cell signalling is altered it results in
diseases such as metabolic disorders, tissue fibrosis, cancer etc.</p><h4 style="line-height: 24px; text-align: justify;">Cancer and cells</h4><p class="MsoNormal" style="line-height: 150%; text-align: justify;"><span class="hgkelc"><span lang="EN">Cancer is a leading cause of death worldwide, accounting for nearly 10 million deaths in 2020.<b> </b></span></span>The major cause of death due to cancer is its ability to “metastasize”. Metastasis is a process in which the cells dislodge from a primary tumour, gain entry into the blood-circulation, travel along the blood vessel, gain entry into the tissue parenchyma at a distant site and establish a new colony which eventually forms a secondary tumour. Though it appears as a straightforward process there are several obstacles that these travellers must overcome in order to reach a new site and flourish. Sadly, only 0.01% of the escaped cells survives the process.</p><p class="MsoNormal" style="line-height: 150%; text-align: justify;"><o:p></o:p></p>
<p class="MsoNormal" style="line-height: 150%; text-align: justify;">Nevertheless, the
metastatic cells are hard to diagnose and harder to treat since they exist in
many different phenotypic states. It is often said that metastasis begins with
Epithelial-to-Mesenchymal transition (EMT) in which the cells acquire
characteristics suitable for invasion such as increased motility, loss of
apical-basal polarity, loss of cell-cell contacts, ability to degrade the ECM
etc. But what exactly is “metastasis”,
and how does it progress? <o:p></o:p></p><p class="MsoNormal" style="line-height: 150%; text-align: justify;"><br /></p><p class="MsoNormal" style="line-height: 150%; text-align: justify;"></p><table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto;"><tbody><tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEj8yFYBBXUQ8G5URXdhUcG5yRAfEQm9MsT54iecM7edCT64xeRUw1XlW6Qe8lxMGBJpvOv9wmgKy5vgJOMwF1YOim9t0pMUhxt2XCsuHcQBToWLyfnoBgUhlIOBjc6dbOFM6kQfLIfYmdOKuASeqYZwwxCKQSYnSzOLswp3GTDt9lw2c16wqVndWA" style="margin-left: auto; margin-right: auto;"><img alt="" data-original-height="580" data-original-width="626" height="297" src="https://blogger.googleusercontent.com/img/a/AVvXsEj8yFYBBXUQ8G5URXdhUcG5yRAfEQm9MsT54iecM7edCT64xeRUw1XlW6Qe8lxMGBJpvOv9wmgKy5vgJOMwF1YOim9t0pMUhxt2XCsuHcQBToWLyfnoBgUhlIOBjc6dbOFM6kQfLIfYmdOKuASeqYZwwxCKQSYnSzOLswp3GTDt9lw2c16wqVndWA=w320-h297" width="320" /></a></td></tr><tr><td class="tr-caption" style="text-align: center;"><i>The (not-so) long road to metastasis</i></td></tr></tbody></table><br /><p></p>
<h4 style="line-height: 150%; text-align: justify;">Stages of metastasis</h4><p class="MsoNormal" style="line-height: 150%; text-align: justify;">The first step
of metastasis begins with the dissemination of the tumour cells from the
primary tumour. The cells can travel either as clusters or as single cells. If
the cells were to travel in clusters it has already failed to comply with the
EMT prerequisite which disallows the cell-cell contacts. However, it has been
clearly documented in breast and lung tumour that cells move in clusters.
Therefore, a complete EMT is not a prerequisite for the metastatic process.
Rather the cells exist in multiple intermediate states lying between epithelial
and mesenchymal pool. Another line of thought is that, among the escaping cohort,
the leader cells (cells in the front of the cluster) might be on the terminal
side of EMT with more destructive traits (ability to degrade the matrix by
proteases) to enable the evasion. The follower cells can therefore follow the
path of the leader cells.<o:p></o:p></p>
<p class="MsoNormal" style="line-height: 150%; text-align: justify;">In the next
stage, the cells enter the circulation to travel to a distant site. These
travellers, known as circulating tumour cells (CTCs), may migrate individually
or as clusters. Life in circulation is equally difficult for these CTCs, for
they need to withstand multiple obstacles on their way in the form of
hydrodynamic flow, shear stress, loss of adhesion to substrate that makes them
vulnerable to clearance by the body’s immune system. Having said that, CTCs shield
themselves by befriending the cells of the circulatory system such as
neutrophils, monocytes, macrophages as well as endothelial cells. These circulatory
cells act as a protective cloak for the CTCs and facilitate their survival. <o:p></o:p></p>
<p class="MsoNormal" style="line-height: 150%; text-align: justify;">Now that the
CTCs have survived their life in circulation, the next step is to invade the
new tissue parenchyma and establish the colonies. This process is known as
extravasation. During extravasation, CTCs traverse the endothelial wall in
process termed as trans endothelial migration. In some cases, CTCs take the
company of the resident cells, especially the monocytes to facilitate
extravasation.<o:p></o:p></p>
<p class="MsoNormal" style="line-height: 150%; text-align: justify;">The propensity
for a particular cell to metastasize to a particular organ may be dependent
upon the tissue of origin, the mechanical and biochemical properties of the new
tissue site, cues for survival advantage.
For example, CTCs entering liver or bone may have a passive entry owing
to their fenestrated architecture whereas those that aim for the brain must
prepare to navigate the tortuous blood-brain barrier which will require a
different set of adaptations. The choice of the distant organ may also be
dependent on the design of the circulatory system. For instance, the metastasis
of colorectal cells to the liver is favoured because the portal vein from gut
empties directly to the liver. <o:p></o:p></p>
<p class="MsoNormal" style="line-height: 150%; text-align: justify;"><br /></p><h4 style="line-height: 150%; text-align: justify;">End of metastatic-journey</h4><p class="MsoNormal" style="line-height: 150%; text-align: justify;">Having completed
the arduous metastatic journey, the CTCs cannot immediately proliferate in the
new tissue. Instead, they exist as dormant tumour cells (DTC) since they are in
an unfamiliar environment and they lack native signals to continue
proliferation. These DTCs may continue to stay quiescent for weeks to years
before they can get survival signals. Being quiescent can also protect the DTCs
from being recognized by the immune system as well as confers chemoresistance
to the cells. Therefore, understanding the dormancy time period may help us
target the quiescent cells that may pose a threat many years later. <o:p></o:p></p>
<p class="MsoNormal" style="line-height: 150%; text-align: justify;">Reports say that
those DTCs that embody traits of cancer stem cells (CSCs) have the survival
advantage since they can rapidly revamp their genetic programs to adapt to the
new environment. The metastatic microenvironment also adds to the ability of
DTCs to establish new colonies. Especially, the fibroblast can signal the DTCs
to engage their integrins for stromal support. In addition, the local ECM
composition and arrangement, stiffness and hypoxia also contribute to the
ability of previously dormant cells to colonize the organ. On the whole, DTCs
stumble through trial and error on different gene expression programs and
adaptive behaviours to effectively survive in the tissue in which they have
landed.<o:p></o:p></p>
<p class="MsoNormal" style="line-height: 150%; text-align: justify;">Though tumour
originates as a result of genetic mutations, the non-genetic adaptive programs of
the native as well as the distant microenvironment should act in concert in order
for the success of the invasion-metastatic cascade. <o:p></o:p></p>
<p><span style="text-align: justify;"> </span> </p><p></p><p> </p><h3 style="text-align: left;">Privita Edwina,</h3><div>Cell-Mechanics Lab,</div><div>AM, IIT Madras</div>Cell Mechanics Laboratory, IIT Madrashttp://www.blogger.com/profile/09776321590790163735noreply@blogger.com0