MMT: A novel therapeutic target for stopping lung cancer

Cancer remains the top leading cause of death worldwide, but treatments are still unsatisfactory. Cancer-associated fibroblast (CAF) is the most prominent stromal component that notably enhances cancer development and progression, but the origins of CAF are still largely unknown which severely limits its therapeutic development. Here, by single-cell RNA sequencing (scRNA-seq), the authors have uncovered a novel phenomenon termed ‘macrophage-myofibroblast transition’ (MMT) in cancer as a direct mechanism of tumour-associated macrophages (TAM) for promoting CAF formation. Importantly, MMT could be therapeutically targeted to suppress formation of protumoral CAF, providing an important rationale for developing new clinical strategy to overcome advanced non-small-cell lung carcinoma.

Lung cancer is still a top killer worldwide

Lung carcinoma is a major cause of death worldwide. There were 5178 new cases of lung cancer in 2017 and it ranked as the top cause of cancer deaths in 2018 in Hong Kong. Surgery, chemotherapy, and radiotherapy have been the mainstays of cancer treatment for decades. However, treatment outcomes still have room for improvement as there are side effects, metastasis, and drug resistance. Cancer cells are versatile and adaptable, leading to primary and secondary treatment resistance. Therapies that target tumour microenvironment show promise as cancer growth, invasion, and metastasis rely on stromal cells. Unexpectedly, only less than 30% of non-small-cell lung carcinoma (NSCLC) patients respond to the conventional T cell-based therapy. Better understanding the tumour microenvironment would discover novel strategies to improve therapeutic outcomes of NSCLC immunotherapy.

Single-cell RNA-sequencing accelerates therapeutic development

Tumour microenvironment is important for tumour formation and progression including angiogenesis (the development of new blood vessels), immunosuppression, metastasis, and drug resistance. However, their components are highly diverse and contain both ‘good’ (anticancer) and ‘bad’ (protumoral) cell subpopulations, making them difficult to target.

Single-cell RNA sequencing is an emerging technology. It extracts the genetic profile of every cell in a tissue sample with high precision. It serves as a perfect tool for the research team to capture the dynamics of the tumour microenvironment. It allows us to observe the dynamics of the tumour microenvironment in great detail with single-cell resolution, and to distinguish between the ‘good’ and ‘bad’ cells which cannot easily be done by the conventional identification method with scalpel and microscope. It helps us to design precise treatment plans, which may lead to the discovery of a new therapeutic strategy for cancer.

A new study conducted by The Chinese University of Hong Kong’s (CUHK) Faculty of Medicine (CU Medicine) dissected the dynamics of lung cancer at single-cell resolution and successfully discovered a new mechanism for de novo generation of cancer-associated fibroblasts via ‘Macrophage-Myofibroblast transition’ (MMT). This is the first study to define a pathogenic role of MMT in cancer.

A novel role of  macrophage-myofibroblast transition in the tumour microenvironment

Early studies by Dr Patrick Tang and Professor Hui-Yao Lan at the Faculty of Medicine, The Chinese University of Hong Kong, revealed a mechanism by which macrophages – specialised cells which help in detecting and destroying bacteria and other dangerous organisms –  are directly transformed into pathogenic myofibroblasts (collagen producing cells in fibrotic kidney) due to long-term overactivation called Macrophage-Myofibroblast Transition (MMT) (Tang et al, 2019). Its potential role in other inflammatory diseases is still largely unknown, including cancer.

The advanced bioinformatics strategies pseudotime and RNA velocity allow us to capture the entire developmental process of the macrophages in lung cancer with the single-cell RNA sequencing dataset, demonstrating a direct transition of tumour-associated macrophages into cancer-associated fibroblasts in the tumour microenvironment via MMT (Tang et al, 2022).

This study further discovered that macrophages can also transform into protumoral cancer-associated fibroblasts in the tumour microenvironment via MMT for promoting tumour growth. The research team had previously discovered the association of MMT in kidney disease progression (Tang et al, 2020). Their preclinical work demonstrated its therapeutic implication for treating lung cancer in this first study to evidence a pathogenic role of MMT in cancer.

Development of MMT-targeted therapy for solid cancers

Immunotherapy is a new hope for cancer patients. Although T-cell based immunotherapy performs well in leukaemia, less than 30% of lung cancer patients respond to it.

Dr Philip Tang found that the level of MMT is associated with the mortality of NSCLC patients, and its presence in other solid cancers, including kidney and liver cancers. MMT was discovered from renal fibrosis in 2014 and there are still a lot of possibilities for this novel mechanism in human diseases. The next step is to develop its precision therapeutics for clinical use.

The team further identified a transcription factor, Smad3, as the key regulator for initiating MMT in non-small-cell lung carcinoma by gene network analysis. They demonstrated that genetic or pharmaceutical inhibition of macrophage Smad3 effectively blocks MMT leading to tumour regression in mice, representing a potential therapeutic target for precisely eliminating the ‘bad’ CAFs. In addition, gene therapy or Chinese medicine would be the potential option for suppressing Smad3 (Xue et al, 2021, Chung et al, 2021).

A better understanding of the tumour microenvironment will improve the efficiency of immunotherapy for solid cancers, possibly by targeting the MMT.

Acknowledgments

This study was supported by the Research Grants Council of Hong Kong (RGC 14106518, 14111019, 14111720); the State Key Laboratory of Translational Oncology; RGC Postdoctoral Fellowship Scheme (PDFS2122-4S06); the Chinese University of Hong Kong’s Faculty Innovation Award (FIA2019/A/01, 4620528); Direct Grant for Research (4054668); and Postdoctoral Fellowship Scheme 2021-22 (NL/LT/PDFS2022/0360/22lt).

Dr Patrick Ming Kuen TANG
Email:
patrick.tang@cuhk.edu.hk
Phone number:
Institute:
Department of Anatomical and Cellular Pathology, Faculty of Medicine, The Chinese University of Hong Kong
Address line 1:
Room 38020, 1/F, Lui Che Woo Clinical Sciences Building
Your City:
Shatin
Your Country or State:
Hong Kong
Your Postal / Zip Code:
999077
References:
Tang, P C, et al (2022). Smad3 Promotes Cancer-Associated Fibroblasts Generation via Macrophage-Myofibroblast Transition. Adv Sci (Weinh), 9, e2101235.

Chung, J Y, et al (2021). AANG: A natural compound formula for overcoming multidrug resistance via synergistic rebalancing the TGF-beta/Smad signalling in hepatocellular carcinoma. J Cell Mol Med, 25, 9805-9813.

Xue, V W, et al (2021). USMB-shMincle: a virus-free gene therapy for blocking M1/M2 polarization of tumor-associated macrophages. Mol Ther Oncolytics, 23, 26-37.

Tang, P M, et al (2020). Neural transcription factor Pou4f1 promotes renal fibrosis via macrophage-myofibroblast transition. Proc Natl Acad Sci U S A, 117, 20741-20752.

Tang, P M, et al (2019). Macrophages: versatile players in renal inflammation and fibrosis. Nat Rev Nephrol, 15, 144-158.

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