Variable Clonal Repopulation Dynamics Influence Chemotherapy Response in Colorectal Cancer

By Antonija Krešo, C. O'Brien, Peter van Galen, O. Gan, F. Notta, Andrew M. K. Brown, Karen Ng, Jing Ma, Erno Wienholds, Cyrille F. Dunant and 6 more. Science, 2012

768 citations recorded by the source corpus.

Dissecting Diversity Solid tumors are composed of functionally diverse tumor cells. The prevailing view is that this "intratumoral heterogeneity" arises from the accumulation of mutations during tumor growth, resulting in multiple genetically defined subclones of cells that respond in different ways to selective pressures such as chemotherapy. Kreso et al. (p. 543, published online 13 December; see the Perspective by Marusyk and Polyak) simultaneously monitored the genetic profiles and growth behavior of human colorectal cancer cells that were serially passaged in mice. Individual tumor cells within a uniform genetic lineage displayed extensive variation in survival, growth dynamics, and response to a chemotherapeutic drug. Thus, additional diversity-generating mechanisms such as epigenetic regulation or microenvironmental variability appear to operate within a genetic clone, endowing a subset of tumor cells with robust survival potential, especially during stress. The functional diversity of heterogeneous tumor cells within tumors cannot be explained by genetic differences alone. [Also see Perspective by Marusyk and Polyak] Intratumoral heterogeneity arises through the evolution of genetically diverse subclones during tumor progression. However, it remains unknown whether cells within single genetic clones are functionally equivalent. By combining DNA copy number alteration (CNA) profiling, sequencing, and lentiviral lineage tracking, we followed the repopulation dynamics of 150 single lentivirus-marked lineages from 10 human colorectal cancers through serial xenograft passages in mice. CNA and mutational analysis distinguished individual clones and showed that clones remained stable upon serial transplantation. Despite this stability, the proliferation, persistence, and chemotherapy tolerance of lentivirally marked lineages were variable within each clone. Chemotherapy promoted the dominance of previously minor or dormant lineages. Thus, apart from genetic diversity, tumor cells display inherent functional variability in tumor propagation potential, which contributes to both cancer growth and therapy tolerance.

Subfields: Cancer Research, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/fdbdaaf2981997e22a46b22264788c835e9e2a93

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. V. Plaks
2. Zena Werb
3. J. Massagué
4. Niwen Kong
5. J. Dick
6. E. Batlle
7. Antonija Krešo
8. Eric S. Lander

In Genetics

1. J. Massagué
2. Thordur Oskarsson
3. Niwen Kong
4. Zena Werb
5. V. Plaks
6. E. Batlle
7. Eric S. Lander

In Molecular Biology

1. E. Batlle
2. Zena Werb
3. V. Plaks
4. J. Massagué
5. Thordur Oskarsson
6. J. Dick
7. Antonija Krešo
8. Levi A. Garraway

Citations in the corpus

• Cancer heterogeneity—a multifaceted view (2013, neutral): “In some instances, more stochastic processes seem to dominate the scene [48,54].”
• The Cancer Stem Cell Niche: How Essential is the Niche in Regulating Stemness of Tumor Cells? (2015, positive): “Therefore, little is known about entering and exiting dormancy, forms of dormancy, and signaling during dormancy, and it remains an overarching challenge for successfully combating many cancers, so better models are needed (Kreso et al., 2013).”
• Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment (2018, background): “For example, chemotherapy can induce the tumor growth of previously relatively dormant or slowly proliferating lineages that still retain potent tumor propagation potential, leading to both cancer growth and drug resistance [87].”
• Homogenous 96-Plex PEA Immunoassay Exhibiting High Sensitivity, Specificity, and Excellent Scalability (2014, background): “Single-cell research is accumulating growing evidence of importance for understanding cancer development, future drug development and for diagnostics aiming to provide the right treatment to the responsive fraction of the patient population [12].”
• Evolution of the cancer stem cell model. (2014, methodology): “…as a number of biological properties that distinguish them from the remainder of tumor cells; not only resistance to treatment (Bao et al., 2006; Li et al., 2008; Tehran-chi et al., 2010) but also evasion of cell death (Majeti et al., 2009; Todaro et al., 2007) and dormancy (Kreso et al., 2013).”
• Lessons from the cancer genome. (2013, positive): “Single-cell analyses have already provided new insights into the evolutionary history of tumors within individual patients and have revealed functional differences across individual tumor cells (Kreso et al., 2013).”