Abstract:Intratumoral heterogeneity in cancers arises from genomic instability and epigenomic plasticity and is associated with resistance to cytotoxic and targeted therapies. We show here that cell-state heterogeneity, defined by differentiation-state marker expression, is high in triple-negative and basal-like breast cancer subtypes, and that drug tolerant persister (DTP) cell populations with altered marker expression emerge during treatment with a wide range of pathway-targeted therapeutic compounds. We show that M… Show more
“…While the model does not capture the rich behavior that may arise from the variable strengths of regulatory interactions in cells in a population or from cell-cell communication, it is a useful first step in understanding the generation and maintenance of phenotypic heterogeneity in cancer cells. Targeting the ability of cancer cells to change phenotypes and generate heterogeneous populations has recently been proposed as a therapeutic strategy for combating drug resistance (Risom et al, 2018). Our model can be a platform to identify putative therapeutic targets for inhibiting the generation, maintenance, and propagation of phenotypic heterogeneity in cancer cells that exhibit EMP.…”
Section: Discussionmentioning
confidence: 99%
“…Spontaneous switching between luminal, basal, and stem-like states has been reported in breast cancer cell lines (Gupta et al, 2011) while androgen-deprivation therapy has been shown to promote transition to a neuroendocrine phenotype in prostate cancer (Hirano et al, 2004;Wright et al, 2003). Cancer cells with different phenotypes can exhibit different sensitivities to various drugs and therapeutic regimens (Risom et al, 2018;Wooten et al, 2018). Therefore, non-genetic mechanisms of phenotypic heterogeneity and plasticity in cancer cells are a fundamental challenge to anti-cancer therapies and an understanding of such mechanisms is essential to the development of effective anti-cancer treatments.…”
Section: Introductionmentioning
confidence: 99%
“…Celià -Terrassa et al observed hysteresis in the dynamics of EMP in multiple normal and cancerous mammary epithelial cell lines and reported a role for hysteretic dynamics in the metastatic ability of cancer cells (Celià-Terrassa et al, 2018). Risom et al showed that drugs targeting specific cellular pathways alter the transitions between epithelial-like and mesenchymal-like states in breast cancer cell lines, thereby establishing phenotypic plasticity as a therapeutically targetable property (Risom et al, 2018). The mechanism responsible for the phenotypic heterogeneity and plasticity in cancer cells, however, remains uncharacterized.…”
Section: Introductionmentioning
confidence: 99%
“…The mechanism responsible for the phenotypic heterogeneity and plasticity in cancer cells, however, remains uncharacterized. Some studies have described phenomenological models of phenotypic plasticity in cancer cells (Chapman et al, 2019;Gupta et al, 2011;Risom et al, 2018). While predictions from these models fit the experimental data reported in the respective studies, such models lack detailed biomolecular mechanistic bases.…”
Epithelial-mesenchymal heterogeneity, wherein cells within the same tumor can exhibit an epithelial, a mesenchymal, or one or more hybrid epithelial-mesenchymal phenotype(s), has been observed across cancer types and implicated in metastatic aggressiveness. Here, we have used computational modeling to show that this heterogeneity can emerge from the noise in the partitioning of RNAs and proteins among the daughter cells during cancer cell division. Our model captures the population-level behavior of murine prostate cancer cells, the hysteresis in the dynamics of epithelial-mesenchymal plasticity, and how hybrid phenotype-promoting factors alter the phenotypic composition of a population. We further used the model to describe the implications of heterogeneity for therapeutics. By linking the dynamics of an intracellular regulatory circuit to the phenotypic composition of a population, the study contributes towards understanding how non-genetic heterogeneity can be generated and propagated from a small, homogeneous population, and towards therapeutic targeting of cancer cell heterogeneity.
“…While the model does not capture the rich behavior that may arise from the variable strengths of regulatory interactions in cells in a population or from cell-cell communication, it is a useful first step in understanding the generation and maintenance of phenotypic heterogeneity in cancer cells. Targeting the ability of cancer cells to change phenotypes and generate heterogeneous populations has recently been proposed as a therapeutic strategy for combating drug resistance (Risom et al, 2018). Our model can be a platform to identify putative therapeutic targets for inhibiting the generation, maintenance, and propagation of phenotypic heterogeneity in cancer cells that exhibit EMP.…”
Section: Discussionmentioning
confidence: 99%
“…Spontaneous switching between luminal, basal, and stem-like states has been reported in breast cancer cell lines (Gupta et al, 2011) while androgen-deprivation therapy has been shown to promote transition to a neuroendocrine phenotype in prostate cancer (Hirano et al, 2004;Wright et al, 2003). Cancer cells with different phenotypes can exhibit different sensitivities to various drugs and therapeutic regimens (Risom et al, 2018;Wooten et al, 2018). Therefore, non-genetic mechanisms of phenotypic heterogeneity and plasticity in cancer cells are a fundamental challenge to anti-cancer therapies and an understanding of such mechanisms is essential to the development of effective anti-cancer treatments.…”
Section: Introductionmentioning
confidence: 99%
“…Celià -Terrassa et al observed hysteresis in the dynamics of EMP in multiple normal and cancerous mammary epithelial cell lines and reported a role for hysteretic dynamics in the metastatic ability of cancer cells (Celià-Terrassa et al, 2018). Risom et al showed that drugs targeting specific cellular pathways alter the transitions between epithelial-like and mesenchymal-like states in breast cancer cell lines, thereby establishing phenotypic plasticity as a therapeutically targetable property (Risom et al, 2018). The mechanism responsible for the phenotypic heterogeneity and plasticity in cancer cells, however, remains uncharacterized.…”
Section: Introductionmentioning
confidence: 99%
“…The mechanism responsible for the phenotypic heterogeneity and plasticity in cancer cells, however, remains uncharacterized. Some studies have described phenomenological models of phenotypic plasticity in cancer cells (Chapman et al, 2019;Gupta et al, 2011;Risom et al, 2018). While predictions from these models fit the experimental data reported in the respective studies, such models lack detailed biomolecular mechanistic bases.…”
Epithelial-mesenchymal heterogeneity, wherein cells within the same tumor can exhibit an epithelial, a mesenchymal, or one or more hybrid epithelial-mesenchymal phenotype(s), has been observed across cancer types and implicated in metastatic aggressiveness. Here, we have used computational modeling to show that this heterogeneity can emerge from the noise in the partitioning of RNAs and proteins among the daughter cells during cancer cell division. Our model captures the population-level behavior of murine prostate cancer cells, the hysteresis in the dynamics of epithelial-mesenchymal plasticity, and how hybrid phenotype-promoting factors alter the phenotypic composition of a population. We further used the model to describe the implications of heterogeneity for therapeutics. By linking the dynamics of an intracellular regulatory circuit to the phenotypic composition of a population, the study contributes towards understanding how non-genetic heterogeneity can be generated and propagated from a small, homogeneous population, and towards therapeutic targeting of cancer cell heterogeneity.
“…Reduction in cellular robustness, cell cycle progression, DNA damage response and induction of replication stress have been proposed as underlying mechanisms of response to BET inhibition (15,(17)(18). BET molecules also regulate cellular plasticity as exemplified by the emergence of drug-tolerant persistent cells with BRD4 dependence and altered differentiation states after MEK and PI3K/mTOR inhibition in TNBC (19). The adaptive responses and therapeutic stress such as DNA-damage associated with inhibition of BET activity provide an unexplored opportunity to discover drug-induced vulnerabilities, which might be exploited with effective combination therapies (20).…”
The development of effective targeted therapies for the treatment of basal-like breast cancers remains challenging. Here, we demonstrate that BET inhibition induces a multi-faceted adaptive response program leading to MCL1 protein-driven evasion of apoptosis in breast cancers. Consequently, co-targeting MCL1 and BET is highly synergistic in in vitro and in vivo breast cancer models. Drug response and genomics analyses revealed that MCL1 copy number alterations, including low-level gains, are selectively enriched in basal-like breast cancers and associated with effective BET and MCL1 co-targeting. The mechanism of adaptive response to BET inhibition involves upregulation of critical lipid metabolism enzymes including the rate-limiting enzyme stearoyl-CoA desaturase (SCD). Changes in the lipid metabolism are associated with increases in cell motility and membrane fluidity as well as transitions in cell morphology and adhesion. The structural changes in the cell membrane leads to re-localization and activation of HER2/EGFR which can be interdicted by inhibiting SCD activity. Active HER2/EGFR, in turn, induces accumulation of MCL1 protein and therapeutic vulnerability to MCL1 inhibitors. The BET protein, lipid metabolism and receptor tyrosine kinase activation cascade is observed in patient cohorts of basal-like and HER2-amplified breast cancers. The high frequency of MCL1 chromosomal amplifications (>30%) and gains (>50%) in basal-like breast cancers suggests that BET and MCL1 co-inhibition may have therapeutic utility in this aggressive subtype.
Cellular phenotype plasticity between the epithelial and mesenchymal states has been linked to metastasis and heterogeneous responses to cancer therapy, and remains a challenge for the treatment of triple‐negative breast cancer (TNBC). Here, we used isogenic human breast epithelial cell lines, D492 and D492M, representing the epithelial and mesenchymal phenotypes, respectively. We employed a CRISPR‐Cas9 loss‐of‐function screen targeting a 2240‐gene ‘druggable genome’ to identify phenotype‐specific vulnerabilities. Cells with the epithelial phenotype were more vulnerable to the loss of genes related to EGFR‐RAS‐MAPK signaling, while the mesenchymal‐like cells had increased sensitivity to knockout of G2‐M cell cycle regulators. Furthermore, we discovered knockouts that sensitize to the mTOR inhibitor everolimus and the chemotherapeutic drug fluorouracil in a phenotype‐specific manner. Specifically, loss of EGFR and fatty acid synthase (FASN) increased the effectiveness of the drugs in the epithelial and mesenchymal phenotypes, respectively. These phenotype‐associated genetic vulnerabilities were confirmed using targeted inhibitors of EGFR (gefitinib), G2‐M transition (STLC), and FASN (Fasnall). In conclusion, a CRISPR‐Cas9 loss‐of‐function screen enables the identification of phenotype‐specific genetic vulnerabilities that can pinpoint actionable targets and promising therapeutic combinations.
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