Bulletin of the American Physical Society
APS March Meeting 2022
Volume 67, Number 3
Monday–Friday, March 14–18, 2022; Chicago
Session T04: Physics of CancerFocus Recordings Available
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Sponsoring Units: DBIO Chair: Yuval Elhanati, Memorial Sloan Kettering Cancer Center Room: McCormick Place W-176C |
Thursday, March 17, 2022 11:30AM - 12:06PM |
T04.00001: Statistical fingerprints of immune selection of tumor cells Invited Speaker: Yuval Elhanati The adaptive immune system plays an evolutionary arms race against pathogens and tumor cells. The constant generation of T cells with novel T cell receptors (TCRs) creates pressure on viral epitopes and cancer neoantigens. In cancer, this process can be analyzed by following both the neoantigens and the immune repertoire through sequencing. On the immune side, it is possible to sequence TCRs from T cells in blood and tumor samples, getting a snapshot of the changing immune system. Selection effects would affect the T cell repertoire diversity, cluster TCRs in amino acid sequence space and change their amino acid statistics, with these changes reflected in TCR samples. I will describe computational methods that can be used to infer immune selection effects from data, based on quantitative analysis of TCRs sequences. We see that changes in the diversity and focusing of the repertoire are indicative of the affect the immune system has on the tumor cells. |
Thursday, March 17, 2022 12:06PM - 12:18PM |
T04.00002: Distinguishing Multicellular from Unicellular Sources of Antifungal Resistance Lesia Guinn, Evan Lo, Gabor Balazsi Multicellular drug resistance is observed in nature and in the clinic in biofilms, flocs, clumps, and tumors. Currently, mechanistic complexity hinders reliable differentiation between unicellular and multicellular sources of drug resistance. Here, we develop a general pipeline for mechanistic drug response interpretation based on growth curve analysis and modeling for two Saccharomyces cerevisiae genetic backgrounds: TBR1 (multicellular, clumping wild-type and unicellular AMN1 deletion mutant) and BY4742 (unicellular wild-type and unicellular AMN1 deletion mutant). The strains in each pair are genetically identical, except for an AMN1 gene deletion. The TBR1 strains represent the effects of both clumping and AMN1 deletion, while the BY4742 strains represent unicellular AMN1 effects. Quantitative analysis and computational modeling of drug-dependent growth curve changes could differentiate between multicellular versus unicellular AMN1-related effects on drug resistance. |
Thursday, March 17, 2022 12:18PM - 12:30PM |
T04.00003: Exploring the dynamical phases of tumor-immune interaction Youyuan Deng, Herbert Levine In the growth of malignant tumor, cancer cells are able to escape from the surveillance of immune cells. Various factors are proposed to explain the immune evasion, such as mechanical barrier to immune cells, insufficiency of nutrient, adverse biochemical environment for immune response. More surprisingly, some immune cells seem to have a pro-tumor role, e.g. by secreting certain growth factor molecules. The tumor-immune microenvironment therefore becomes a complicated ecological system. We built a simplified dynamical system modeling these interactions, and try to map distinct dynamical states to biological observations. We also try to provide a perspective on some evident differences between tumor-immune microenvironment and macroscopic natural predator-prey systems, such as the absence of oscillatory phase in the former. |
Thursday, March 17, 2022 12:30PM - 1:06PM |
T04.00004: Predicting clonal evolution in cancer under immune selection Invited Speaker: Marta Luksza Immune editing of neoantigens is crucial for the success of immunotherapies, but it is still unknown to what extent the immune system naturally edits evolving tumors and what is the fitness cost associated with the presence of neoantigens. Here we develop a biophysically grounded neoantigen quality model, which quantifies the immunogenicity of tumor neoantigens. We use the model to define the fitness of tumor clones as a combination of negative selection due to immune recognition and positive selection due to oncogenic mutations. We investigate how pancreatic cancers – a lowly mutated, poorly immunogenic cancer, largely presumed to not be subject to immunoediting – evolve over 10 years. With the fitness model, we show that long-term pancreatic cancer survivors evolve new clones of markedly lower immune fitness cost, to indicate clones with high-quality neoantigens are negatively selected. Importantly, the fitness model predicts the clonal composition of recurrent tumors of the patients. Thus, we submit longitudinal evidence that the human immune system naturally edits neoantigens. Furthermore, we present a model that describes how tumor cell populations evolve under immune pressure over time, with implications for cancer biology and therapy. |
Thursday, March 17, 2022 1:06PM - 1:18PM |
T04.00005: Effect of flow on chemical sensing for directed cell migration Soutick Saha, Hye-ran Moon, Bumsoo Han, Andrew Mugler Directed cell migration, including in cancer metastasis, occurs in response to a complex microenvironment consisting of multiple chemical and mechanical cues. Therefore, it is important to understand cell migration in response to multiple cues present simultaneously in the environment. But most experiments, particularly on cancer cell migration, have been performed using single cues. In this study we analyze cancer cell migration in response to the simultaneous presence of fluid flow and a chemical attractant. We find that when the chemical signal is present above a detectable limit, a cell always follows the chemical gradient, not the flow, and that the cells can only sense the flow when the chemical signal is very weak. We explain this behavior with a mathematical model, and we also map the system to a simple logical circuit that describes the decision-making underlying this migratory behavior. |
Thursday, March 17, 2022 1:18PM - 1:30PM |
T04.00006: Statistical dynamics of tumor initiation and progression Sidhartha Goyal, Sumaiyah Rehman, Catherine O'Brien Cancer cells are generally not well defined molecularly or phenotypically. How cellular heterogeneity of tumor initiating cells (TICs) fuels tumor growth remains an open question. To address this challenge we analyzed cellular dynamics in human colorectal cancer samples by following the fate of distinct tumor cells in vivo. Consistent with similar recent experiments we find clonal dominance with a broad distribution of clonal contributions (more than 100-fold difference) across the successful lineages, which has been suggested to constitute evidence for cellular heterogeneity among TICs, i.e. some cells are better than others at forming tumors. Surprisingly, outcomes of mixing experiments between dominant monoclonal tumors and polyclonal tumors showed a pattern where the fractional contribution from the monoclonal tumor was below its injected fraction. To address this puzzle, we have suggested a model with stochastic fate for TICs, which not only explains differences in clonal composition among different lineages in tumors, but also the surprising patterns found in mixing experiments. |
Thursday, March 17, 2022 1:30PM - 1:42PM |
T04.00007: Incorporating the role of a biomarker in a mathematical model to study drug resistance. Mitra Shojania Feizabadi Drug resistance is one the major challenges in cancer treatment. In some experimental and clinical studies on breast cancer, a correlation between the degree in which cancer cells response to some chemotherapeutic drugs is linked to the level of the expression of one of the intracellular proteins, Tau protein. These studies suggest that the overexpression of Tau protein in breast cancer cells can be considered as a promising biomarker to predict drug resistance in those cells. In this study, our previously reported mathematical model of cancer dynamics in the presence of drug resistance is expanded to incorporate one possible role of a biomarker. By relying on the outcomes of a series of numerical analyses, the work discusses different cases in which the functional mechanism of a biomarker can provide critical insight that can potentially lead to revising therapeutic strategies, and consequently more successful treatment outcomes. |
Thursday, March 17, 2022 1:42PM - 1:54PM |
T04.00008: Mathematical model for karyotype evolution describing mouse pretumor and tumor cells Lucija Tomašić, Ivana Ban, Marianna Trakala, Iva Tolić, Nenad Pavin During cell division, mis-segregation of duplicated chromosomes generates cells with perturbed karyotypes which after multiple cell divisions lead to tumor tissues. Experimentally it was found that in living mouse with enhanced chromosome mis-segregation, chromosome gains dominate over chromosome losses both in pretumor and tumor tissues. Additionally, it was also shown that tumor cells predominantly have extra copies of chromosome 15, as compared to other chromosomes. However, what causes observed gains over losses and why chromosome 15 predominantly appears with extra copies is still unknown. By developing a mathematical model, that includes chromosome mis-segregation, apoptosis and proliferation, we study karyotype evolution over multiple generations. By comparing our model results with experimental data for pretumor cells, we found that observed dominating chromosome gains over losses can be explained by pronounced apoptosis or slower proliferation of cells with chromosome losses. For explaining excess of chromosome 15 in tumor cells, our model predicts that these cells proliferate two fold faster than cells with two copies of chromosome 15. Based on this we conclude that enhanced proliferation is the main driver of tumor karyotype evolution. |
Thursday, March 17, 2022 1:54PM - 2:06PM |
T04.00009: Cancer Cell Migration Directed by Mechanochemical Dual Guidance Pedram Esfahani, Bo Sun, Herbert Levine In this study, we quantified the effectiveness of ROCK-inhibitors (Y27632) and Rho-activators (CN03) on the cell migration directionality in presence of mechanochemical dual guidance. We incorporated a flow-induced ECM alignment in 3D chemotaxis assays to investigate cancer cell motility in 3D under the presence of a mechanical and a chemical guidance simultaneously. For the baseline, by measuring the coherency of the ECM in a small region around a target cell and applying a variety of serum gradients across the region, we can quantify the probability distribution of the direction of the MDA-MB-231 cancer cells migration with respect to the angle between the cues. |
Thursday, March 17, 2022 2:06PM - 2:18PM |
T04.00010: How cytoskeletal forces alter nuclear protein and chromatin distributions during confined cell migration. Sirine A Amiri The ability of cells to squeeze through constrictions is affected by the stiffness of the large and rigid nucleus, and is a hallmark of metastases and cancer progression. During this process, a sufficient force needs to be applied by the cytoskeleton to the nucleus. We address here the mechanism of nucleus pulling during cell translocation through openings smaller than the nuclear diameter. We observe its consequences on the chromatin distribution. We showed that nuclear envelope proteins, such as nesprins, which mechanically link the actin cytoskeleton to the nuclear membrane, move towards the front of the nucleus surface, a movement that depends on pulling forces, especially through the actin cytoskeleton [1]. Likewise, SUN proteins move towards the nucleus front whereas the lamin network, right underneath the nucleus membrane, does not polarize. The lamin shell wrinkles during nucleus translocation and chromatin densifies at the center of the nucleus. Our results allow for deciphering the orchestration of mechanotransduction in the nucleus and suggest an active/passive role repartition among those proteins. The next step will be to characterize and quantify this repartition, in particular when motility is increased. |
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