Deciphering intratumoral heterogeneity using integrated clonal tracking and single-cell transcriptome analyses

Contreras-Trujillo, Humberto; Eerdeng, Jiya; Akre, Samir; Du, Jie; Contreras, Jorge L.; GALA, BASIA; Vergel-Rodriguez, Mary C; Lee, Yeachan; Jorapur, Aparna; Andreasian, Areen; Harton, Lisa; Bramlett, Charles; Nogalska, Anna; Xiao, Gang; Lee, Jae Woong; Chan, Lai N.; Müschen, Markus; Merchant, Akil; Lu, Rong

doi:10.1038/s41467-021-26771-1

Cited by 20 publications

(9 citation statements)

References 69 publications

(81 reference statements)

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“…To reveal the molecular mechanisms underlying the distinct responses of HSC clones to MPP cotransplantation as shown in our study (Figs. 2 – 5 ), future studies integrating cellular barcoding technology and massively parallel single-cell RNA sequencing could enable simultaneous investigations into clonal trajectories and corresponding molecular profiles 39 .…”

Section: Discussionmentioning

confidence: 99%

Lineage tracking to reveal the fate of hematopoietic stem cells influenced by Flk2− multipotent progenitors after transplantation

Wang

Vergel-Rodriguez

et al. 2023

Exp Mol Med

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After transplantation, hematopoietic stem cells (HSCs) sustain blood cell regeneration throughout the patient’s life. Recent studies suggest that several types of mature blood cells provide feedback signals to regulate HSC fate. However, the potential feedback effect of hematopoietic progenitor cells has not been characterized to date. The present investigation demonstrated that multipotent progenitors (MPPs) promoted T cell production of HSCs when both cell types were cotransplanted in mice. Using genetic barcodes to track individual HSCs in mice, we found that the increased T cell production by HSCs was associated with the combined effects of altered lineage bias and clonal expansion during HSC differentiation. We showed that MPP and HSC co-transplantation promoted the multilineage differentiation of HSCs in the short term while preserving lymphoid-specialized HSC differentiation in the long term. Our findings indicate that MPPs derived from HSCs regulate the fate of HSCs after bone marrow transplantation.

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Section: Discussionmentioning

confidence: 99%

Lineage tracking to reveal the fate of hematopoietic stem cells influenced by Flk2− multipotent progenitors after transplantation

Wang

Vergel-Rodriguez

et al. 2023

Exp Mol Med

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“…Non-genetic mechanisms may also contribute to resistance to novel forms of targeted agents (e.g., PROTACs that act to degrade, rather than inhibit, targeted proteins) ( 169 ). In addition, with recent applications of single-cell sequencing techniques, dissection of intratumoral heterogeneity has helped identify distinctive targets and pathways in different clusters (clones) of tumor cells within the same tumor ( 170 , 171 ). On the one hand, this could explain why many agents targeting a single oncoprotein (even though it drives malignant transformation or oncogenesis) presumably existed in dominant clones are not sufficient enough to kill the meaningful number of tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Dual-Targeted Therapy Circumvents Non-Genetic Drug Resistance to Targeted Therapy

et al. 2022

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The introduction of various targeted agents into the armamentarium of cancer treatment has revolutionized the standard care of patients with cancer. However, like conventional chemotherapy, drug resistance, either preexisting (primary or intrinsic resistance) or developed following treatment (secondary or acquired resistance), remains the Achilles heel of all targeted agents with no exception, via either genetic or non-genetic mechanisms. In the latter, emerging evidence supports the notion that intracellular signaling pathways for tumor cell survival act as a mutually interdependent network via extensive cross-talks and feedback loops. Thus, dysregulations of multiple signaling pathways usually join forces to drive oncogenesis, tumor progression, invasion, metastasis, and drug resistance, thereby providing a basis for so-called “bypass” mechanisms underlying non-genetic resistance in response to targeted agents. In this context, simultaneous interruption of two or more related targets or pathways (an approach called dual-targeted therapy, DTT), via either linear or parallel inhibition, is required to deal with such a form of drug resistance to targeted agents that specifically inhibit a single oncoprotein or oncogenic pathway. Together, while most types of tumor cells are often addicted to two or more targets or pathways or can switch their dependency between them, DTT targeting either intrinsically activated or drug-induced compensatory targets/pathways would efficiently overcome drug resistance caused by non-genetic events, with a great opportunity that those resistant cells might be particularly more vulnerable. In this review article, we discuss, with our experience, diverse mechanisms for non-genetic resistance to targeted agents and the rationales to circumvent them in the treatment of cancer, emphasizing hematologic malignancies.

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“…Fates of cancer cells with recent shared ancestry are closely intertwined, showing aligned drug responses 33 and preferential site of metastasis 34,35 . Cells of the same progeny, at least until a couple of generations apart, also present similar expression profiles 36,37 .…”

Section: Discussionmentioning

confidence: 99%

Tracing back primed resistance in cancer via sister cells

Dai

Zheng

Falco

et al. 2022

Preprint

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Exploring non-genetic evolution of cell states during cancer treatments has become attainable by recent advances in lineage-tracing methods coupling cell states to future fates. However, transcriptional changes that drive pre-treatment cells into resistant fates may be subtle, necessitating high resolution analysis. We developed ReSisTrace that uses shared transcriptomic features of synchronised sister cells to predict the states that prime treatment resistance, and allows identification of asymmetric features that drive phenotypic heterogeneity. Applying ReSisTrace in ovarian cancer cells revealed that BRCAness transcriptional signatures are associated with pre-existing vulnerability not only to olaparib and carboplatin treatments, but also to natural killer cell-mediated cytotoxicity. This novel connection between DNA repair defect and susceptibility to natural killer cells was further validated both functionally and in a clinical cohort. The high-resolution analysis by ReSisTrace enables resolving pre-existing transcriptional features of treatment vulnerability, facilitating molecular patient stratification for personalised therapies.

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Deciphering intratumoral heterogeneity using integrated clonal tracking and single-cell transcriptome analyses

Cited by 20 publications

References 69 publications

Lineage tracking to reveal the fate of hematopoietic stem cells influenced by Flk2− multipotent progenitors after transplantation

Lineage tracking to reveal the fate of hematopoietic stem cells influenced by Flk2− multipotent progenitors after transplantation

Dual-Targeted Therapy Circumvents Non-Genetic Drug Resistance to Targeted Therapy

Tracing back primed resistance in cancer via sister cells

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