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context should also be taken into consideration in reconciling the opposing EMT-promoting and anti-
autophagy effects of miRNA-dependent loss of PTEN. Could miR-21 and miR-93 also regulate other targets
concurrently to yield the phenotype observed? We also noted that several of these studies demonstrate
induction of cell migration/invasion by overexpressing miR-21 or miR-93 in cancer cells grown in the
tissue culture setting [64,67] . Unlike the circulating DTCs in a living organism, cancer cells cultured in
vitro are never short of nutrient supply. It is perhaps not surprising that the need to trigger pro-survival
autophagy in these cancer cells might be over-written by external culture conditions in vitro. Alternatively,
miRNAs like miR-21 and miR-93 may serve as sensors of favorable distant niches. As the DTCs extravasate
at their destination sites, these miRNAs could respond to the new environment that provides nutrients to
fuel the transition from micro- to macro-metastasis. Similarly, there exists tumor suppressive miRNAs
that have been implicated in autophagy activation but yet inhibit cancer growth and metastasis. These
miRNAs, including let-7, miR-7, miR-16 and miR-205, have been shown to be less abundant in tumors [74-82] .
Their absence in DTCs at micrometastasis sites might be crucial to cell survival, as autophagy genes will
remain activated to ensure nutrient supply until conditions of the new environment turn favorable for
macrometastasis.

PRECISION TARGETING OF MIRNA-AUTOPHAGY SIGNALING NODES BY SMALL MOLECULE

AND RNA-BASED THERAPEUTICS
To date, cytotoxic chemotherapy remains the most widely used neoadjuvant or adjuvant treatment
[88]
modality against cancers despite its association with a host of unpredictable side effects . In addition, a
recent study demonstrates that cytotoxic chemotherapeutics broadly used in neoadjuvant cancer therapy
[89]
elicit tumour-derived extracellular vesicles with enhanced pro-metastatic capacity . Hence, precise
targeting of metastasis-enabling cellular processes, such as autophagy, is warranted and could synergize
with chemotherapy to maximize therapeutic efficacy. For instance, small molecule inhibitor targeting of
focal adhesion kinase (commonly known as FAK) activates the SRC kinase and thereby inhibits autophagy,
which in turn, prevents the migration of SRC-driven metastatic tumor cells [90,91] . Given the complexity
of signaling pathways driving metastasis, a systematic framework for the development of effective anti-
[92]
metastatic drugs has recently been proposed .
Of late, RNA-based therapies (antisense, siRNAs, aptamers, miRNA mimics/anti-miRs and synthetic
mRNA) have shown great promise as powerful adjuncts to the drug developer’s existing toolbox of small
[93]
molecules and biologics . Notably, miRNA-based therapeutics gained much attention in translational
medicine and are currently tested in various Phase I and II clinical trials. miRNA-based therapeutics
is broadly categorized as miRNA mimics and inhibitors of miRNAs (also known as anti-miRs or
antagomiRs). miRNA mimics, in the form of synthetic double-stranded small RNA molecules that match
the corresponding miRNA sequence, are aimed at replenishing the lost miRNA expression in diseases.
Most of the commercial miRNA mimics are often modified by methylation of the passenger strand to
increase their stability. AntagomiRs, on the other hand, are antisense oligonucleotides that are single-
stranded and can be chemically-modified (with locked nucleic acids or with 2'-O-methoxyethylribonucle
[94]
oside) to increase affinity for their miRNA targets to block their functions . To prevent degradation by
RNases in biofluids or in the endocytic compartment of cells, these miRNA therapeutics are frequently
stabilized by oligonucleotide chemistry (as mentioned above or by adding phosphorothioate-like groups)
or encapsulated in delivery vehicles, such as poly(lactide-co-glycolide) particles, neutral lipid emulsions,
[95]
synthetic polyethylenimine, cyclodextrin, chitosan, etc., . For instance, epidermal growth factor (EGFR)-
targeted, EnGeneIC delivery vehicle-packaged miR-16 mimics have been tested in a Phase I clinical trial
(NCT02369198) in which acceptable safety profile and on-target activity of these miR-16 mimics have been
demonstrated in patients with malignant pleural mesothelioma . In addition, two other clinical trials
[96]
(NCT02862145 and NCT01829971), involving the use of miR-34a mimics to treat primary liver cancer, small