The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research. Previously known as our Top 10 Cancer Research Publications, it is curated by the Board of the European Association for Cancer Research (EACR).
The list below appears in no particular order, and the summary information has been provided by the authors unless otherwise indicated.
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Álvarez-Varela, A., Novellasdemunt, L., Barriga, F.M. et al. Nat Cancer 3, 1052–1070 (2022).
doi: 10.1038/s43018-022-00402-0.
“This is a great example how using organoids systems can predict responses of cancer patients or in this case, relapse after treatment.” EACR Board
Summary of findings
Nearly 2 million new cases of colorectal cancer (CRC) are diagnosed worldwide each year. Chemotherapy is part of the standard of care for patients with advanced CRC. In many cases, this treatment is initially effective yet many patients relapse after intended curative therapeutic regimes. Tumor cells capable of resisting chemotherapy, the so-called Drug Tolerant Persister cells (DTPs), are the culprits of disease relapse after treatment but the identity and features of these tumor cell population remain poorly characterized.
In this Nature Cancer paper, Álvarez-Varela et al. from the Batlle lab at IRB Barcelona reveal the identity of a group of chemotherapy resistant cells in both murine tumor models and human CRC patients. These DTPs express the gene Mex3a, are stem cell-like cells and, as a result of adaptation to a suboptimal niche environment, they reside in a state of latency that spares them from death by conventional chemotherapy. Lineage tracing experiments combined with single-cell profiling showed that upon treatment, Mex3a+ DTPs adopt a state reminiscent of intestinal fetal progenitors and regenerate the tumor once chemotherapy treatment ceases.
Mex3a encodes an RNA-binding protein that regulates protein translation and Álvarez-Varela and colleagues demonstrate that CRCs lacking the Mex3a gene are unable to transition to the fetal-like state. Instead, they differentiate towards a secretory intestinal phenotype that is vulnerable to chemotherapy. Overall, these findings open up the possibility of improving the outcome of chemotherapy in CRC by implementing strategies that target Mex3a+ DTPs.
Future Impact
A large proportion of CRC patients relapse after treatment with chemotherapy. This work paves the way for the development of drugs to eliminate dormant Mex3a+ cells, which would have a synergistic effect with chemotherapy to improve survival rates.
Additionally, since the MEX3A gene is required for tumour cells to relapse after chemotherapy, eradication of Mex3a+ cells could be done by targeting the MEX3A protein. Therefore, this paper offers candidate strategies to improve the clinical benefit of standard chemotherapy.
