How Spatial Transcriptomics Sheds Light on Tumor Microenvironments

Cancer remains one of the leading causes of morbidity and mortality worldwide. According to the World Health Organization (WHO), there were an estimated 20 million new cancer cases and almost 10 million cancer-related deaths in 2022. The future outlook is also worrisome, with the global burden of cancer expected to rise to 33 million projected incidences (a 65% increase) and 18 million projected deaths (an 80% increase) by 2050.

Even though cancer treatment has advanced extensively with development of immunotherapy and targeted therapeutics, leading to substantial improvement in survival rates and quality of life for patients, some challenges like drug resistance, tumor heterogeneity and complexity continue to severely impact its efficacy. Improving outcomes for cancer patients globally, requires extensive and collaborative research efforts to better comprehend its inherent heterogeneity and tumor microenvironment.

This blog is an inquiry into the complex ecosystem of tumor microenvironment (TME), and posits that it is crucial to explore the formation, dynamic evolution and diverse components constituting this microenvironment in order to better understand its role in cancer progression. It also focuses on the recent breakthroughs and key technological innovations which have enabled and advanced human ability to study this complex ecosystem.

2. Current Insights

2.1 Formation and Evolution of the TME

The formation and evolution of the tumor microenvironment (TME) is a highly dynamic process that begins at the earliest stages of tumorigenesis and continues to adapt as the tumor progresses. At the onset of tumor, cancer cells begin to recruit and reprogram surrounding non-cancerous cells, including immune cells and stromal cells. This is orchestrated through various forms of communication, like direct cell-cell contact and the release of paracrine signals such as cytokines kines, chemokines, and growth factors. These signals help in recruiting supportive cells to the tumor site, which guide the formation and evolution of the TME through various mechanisms. These mechanisms include remodeling of the extracellular matrix (ECM) and immune landscape (to create a tumor supportive environment), along with formation of the TME vasculature( to meet the tumor’s demand for oxygen and nutrients). These dynamic changes in the TME are critical for the tumor's ability to grow, invade, and eventually metastasize to distant organs. Understanding these processes is essential for developing targeted therapies that can disrupt the tumor’s interactions with its microenvironment and enhance treatment outcomes for patients.

2.2 Key Components

TME is a complex ecosystem, composed of various cellular and acellular components. The key cellular components include both cancer and non-cancerous cell types. Cancer cells include not only the primary malignant tumor cells , but also cancer stem cells (CSCs) that possess the properties of normal stem cells to self-renew and differentiate into various cell types. These CSCs are highly tumorigenic and are believed to be a major factor in tumor recurrence and metastasis. Non-cancerous cells were previously thought to be bystanders, but are now known to engage in reciprocal communication with tumor cells to drive tumor initiation, progression, and metastasis. For instance, the large diversity of immune cell types in the TME, adopt distinct functions and can either suppress or promote tumor growth. Cytotoxic CD8+ T cells and natural killer (NK) cells are key players in anti-tumor immunity, which recognize and kill cancer cells. However, tumors also recruit immunosuppressive cells like regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), which inhibit the activity of the cytotoxic cells. Tumor-associated macrophages (TAMs) are also formed through the differentiation of circulating monocytes that are recruited into the TME. Exposure to different factors (IL-10, TGF-β, and M-CSF) secreted in the TME can polarize these cells into a tumor supportive, and immunosuppressive phenotype.

The stromal compartment of the TME includes various non-immune cells like cancer-associated fibroblasts (CAFs), endothelial cells, and pericytes. CAFs are the most well studied cell types that exhibit enormous phenotypic plasticity. They support tumor progression through various mechanisms, including remodeling of the ECM to facilitate tumor growth and invasion, secretion of various growth factors that support tumor cell proliferation, survival, and angiogenesis, as well as secretion of cytokines that recruit immunosuppressive cell types like Tregs and MDSCs. Tumor endothelial cells (TECs) perform the crucial function of nourishing the tumor by forming abnormal, leaky blood vessels that supply the tumor with nutrients and oxygen, and also allow tumor cells to migrate to other parts of the body and metastasize. Tumor ECs also express increased levels of inhibitory immune checkpoint molecules, which contribute to immunosuppression. Pericytes stabilize blood vessels and are co-opted by the tumor to promote vessel maturation in the TME. Finally, depending on the cancer type, tissue resident cell types like adipocytes, neurons and nerve fibers may also play a critical role in the TME. For example, adipocytes are often found in the TME of ovarian cancer cases where the tumor has metastasized to the omentum, a fatty tissue in the abdominal cavity. These adipocytes provide energy and signaling to the molecules that facilitate tumor growth. On the other hand, Neurons and nerve fibers are commonly found in pancreatic ductal adenocarcinoma (PDAC), where they contribute to the aggressive nature of the disease.

The key acellular components of the TME include the extracellular matrix (ECM), soluble factors like cytokines,metabolites and physiological features like hypoxia. The ECM provides structural support through proteins like collagen and fibronectin, while matrix metalloproteinases (MMPs) remodel the ECM to facilitate tumor invasion. Soluble factors, including cytokines like IL-6 and TNF-α, chemokines such as CXCL12, and growth factors like VEGF, regulate immune response, promote angiogenesis, and drive cell proliferation. Metabolites such as lactic acid, a byproduct of altered tumor metabolism, create an acidic environment that supports immune evasion. Exosomes and other extracellular vesicles (EVs) transport bioactive molecules, which aid immune modulation, metastasis, and intercellular communication. Additionally, hypoxia, resulting from poor tumor vascularization, stabilizes hypoxia-inducible factors (HIFs) that promote angiogenesis and metabolic adaptation.

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